Park So Youn, Shin Hwa Kyoung, Lee Won Suk, Bae Sun Sik, Kim Koanhoi, Hong Ki Whan, Kim Chi Dae
Department of Pharmacology, School of Medicine, Pusan National University, Gyeongsangnam-do 50612, Republic of Korea.
Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongsangnam-do 50612, Republic of Korea.
Oncotarget. 2017 Nov 30;8(66):110380-110391. doi: 10.18632/oncotarget.22777. eCollection 2017 Dec 15.
Psychosis is reported over 30% of patients with Alzheimer's disease (AD) in clinics. Aripiprazole is an atypical antipsychotic drug with partial agonist activity at the D dopamine and 5-HT receptors with low side-effect profile. We identified aripiprazole is able to overcome the amyloid-β (Aβ)-evoked neurotoxicity and then increase the cell viability. This study elucidated the mechanism(s) by which aripiprazole ameliorates Aβ1-42-induced decreased neurite outgrowth and viability in neuronal cells. Pretreatment with aripiprazole increased Brain-derived neurotrophic factor (BDNF) mRNA and protein expressions in N2a cells. Additionally, phosphorylated casein kinase 2α at Y 255 (P-CK2α) was increased in time- and concentration-dependent manners. Furthermore, Aβ1-42-induced decreased BDNF and P-CK2α expression were increased over control level by aripiprazole. Subsequently, Aβ1-42-induced decreased levels of phosphorylated glycogen synthase-3β at Ser9 (P-GSK-3β) and nuclear P-β-catenin (Ser675) were elevated by aripiprazole, which were inhibited by K252A (inhibitor of BDNF receptor) and tetrabromocinnamic acid (TBCA, CK2 inhibitor), indicating that BDNF and P-CK2α activation are implicated in the aripiprazole effects. Expressions of cyclin D1 and insulin-like growth factor 2 (IGF2) mRNA were increased by aripiprazole; even in the presence of Aβ1-42, which was blocked by K252A and TBCA. In CK2α gene-silenced N2a cells, aripiprazole failed to increase P-GSK-3β and P-β-catenin expressions. Consequently, aripiprazole ameliorated Aβ1-42-induced attenuation of neurite elongation in HT22 cells, and this effect was blocked by both TBCA and imatinib. Decreased viability induced by Aβ1-42 was recovered by aripiprazole. These findings provide evidence supporting that aripiprazole can provide an effective therapeutic strategy against Aβ-induced neurotoxicity in AD-associated psychosis.
临床研究报告显示，超过30%的阿尔茨海默病（AD）患者会出现精神病症状。阿立哌唑是一种非典型抗精神病药物，对D多巴胺受体和5-羟色胺受体具有部分激动剂活性，且副作用较小。我们发现阿立哌唑能够克服β-淀粉样蛋白（Aβ）诱发的神经毒性，进而提高细胞活力。本研究阐明了阿立哌唑改善Aβ1-42诱导的神经元细胞神经突生长减少和活力降低的机制。用阿立哌唑预处理可增加N2a细胞中脑源性神经营养因子（BDNF）的mRNA和蛋白表达。此外，Y255位点磷酸化的酪蛋白激酶2α（P-CK2α）以时间和浓度依赖性方式增加。此外，阿立哌唑使Aβ1-42诱导的BDNF和P-CK2α表达降低恢复至对照水平以上。随后，阿立哌唑提高了Aβ1-42诱导的Ser9位点磷酸化糖原合酶-3β（P-GSK-3β）和核内P-β-连环蛋白（Ser675）水平的降低，而K252A（BDNF受体抑制剂）和四溴肉桂酸（TBCA，CK2抑制剂）可抑制这种作用，表明BDNF和P-CK2α的激活与阿立哌唑的作用有关。阿立哌唑增加了细胞周期蛋白D1和胰岛素样生长因子2（IGF2）的mRNA表达；即使在存在Aβ1-42的情况下也是如此，而K252A和TBCA可阻断这种增加。在CK2α基因沉默的N2a细胞中，阿立哌唑未能增加P-GSK-3β和P-β-连环蛋白的表达。因此，阿立哌唑改善了Aβ1-42诱导的HT22细胞神经突伸长减弱，而TBCA和伊马替尼均可阻断这种作用。阿立哌唑恢复了Aβ1-42诱导的细胞活力降低。这些发现为阿立哌唑可提供一种有效的治疗策略来对抗AD相关精神病中Aβ诱导的神经毒性提供了证据支持。
